Cardiovascular Autonomic Dysfunction in Children and Adolescents With Rett Syndrome

Kumar, Ajay; Jaryal, Ashok Kumar; Gulati, Sheffali; Chakrabarty, Biswaroop; Singh, Akanksha; Deepak, Kishore Kumar; Pandey, R M; Gupta, Neerja; Sapra, Savita; Kabra, Madhulika; Khajuria, Rajni

doi:10.1016/j.pediatrneurol.2017.01.010

Cited by 23 publications

(37 citation statements)

References 22 publications

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“…A lower RMSSD, which is correlated with lower parasympathetic activity (DeGiorgio et al 2010), suggests that parasympathetic activity in particular is decreased in adolescents born preterm. Lower HRV is well documented as being associated with higher cardiovascular disease risk and worse health outcomes in adults (Liao et al 1997;Dekker et al 2000;Evrengul et al 2006), with evidence of a link with disease in children also (Baum et al 2013;Kumar et al 2017). Our findings open the door for further study of autonomic function in this otherwise healthy population.…”

Section: Heart Rate Variability (R-r Intervals)supporting

confidence: 55%

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Impaired autonomic function in adolescents born preterm

et al. 2018

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Preterm birth temporarily disrupts autonomic nervous system (ANS) development, and the long‐term impacts of disrupted fetal development are unclear in children. Abnormal cardiac ANS function is associated with worse health outcomes, and has been identified as a risk factor for cardiovascular disease. We used heart rate variability (HRV) in the time domain (standard deviation of RR intervals, SDRR; and root means squared of successive differences, RMSSD) and frequency domain (high frequency, HF; and low frequency, LF) at rest, as well as heart rate recovery (HRR) following maximal exercise, to assess autonomic function in adolescent children born preterm. Adolescents born preterm (less than 36 weeks gestation at birth) in 2003 and 2004 and healthy age‐matched full‐term controls participated. Wilcoxon Rank Sum tests were used to compare variables between control and preterm groups. Twenty‐one adolescents born preterm and 20 term‐born controls enrolled in the study. Preterm‐born subjects had lower time‐domain HRV, including SDRR (69.1 ± 33.8 vs. 110.1 ± 33.0 msec, respectively, P = 0.008) and RMSSD (58.8 ± 38.2 vs. 101.5 ± 36.2 msec, respectively, P = 0.012), with higher LF variability in preterm subjects. HRR after maximal exercise was slower in preterm‐born subjects at 1 min (30 ± 12 vs. 39 ± 9 bpm, respectively, P = 0.013) and 2 min (52 ± 10 vs. 60 ± 10 bpm, respectively, P = 0.016). This study is the first report of autonomic dysfunction in adolescents born premature. Given prior association of impaired HRV with adult cardiovascular disease, additional investigations into the mechanisms of autonomic dysfunction in this population are warranted.

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Section: Heart Rate Variability (R-r Intervals)supporting

confidence: 55%

“…; Kumar et al. ). Our findings open the door for further study of autonomic function in this otherwise healthy population.…”

Section: Discussionmentioning

confidence: 99%

Impaired autonomic function in adolescents born preterm

et al. 2018

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“…Independent of disease stage, subsets of patients also experience gastrointestinal problems (Motil et al 2012), abnormal cardiorespiratory coupling (Kumar et al 2017), decreased bone density (Shapiro et al 2010), early-onset osteoporosis (Haas et al 1997), bruxism (Alpoz et al 1999), dyslipidaemia (Justice et al 2013; Segatto et al 2014), inflammation of the gallbladder (Anderson et al 2014), scoliosis (Anderson et al 2014), urological dysfunction (Ward et al 2016), and sleep disturbances (Young et al 2007). Additionally, RTT patients have an increased incidence of unexpected death, and often die due to respiratory infection, cardiac instability, and respiratory failure (Laurvick et al 2006; Anderson et al 2014).…”

Section: Understanding and Developing Therapies For Rare Disordersmentioning

confidence: 99%

Treating Rett syndrome: from mouse models to human therapies

Vashi

Justice

2019

Mamm Genome

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Rare diseases are very difficult to study mechanistically and to develop therapies for because of the scarcity of patients. Here, the rare neuro-metabolic disorder Rett syndrome (RTT) is discussed as a prototype for precision medicine, demonstrating how mouse models have led to an understanding of the development of symptoms. RTT is caused by mutations in the X-linked gene methyl-CpG-binding protein 2 ( MECP2 ). Mecp2- mutant mice are being used in preclinical studies that target the MECP2 gene directly, or its downstream pathways. Importantly, this work may improve the health of RTT patients. Clinical presentation may vary widely among individuals based on their mutation, but also because of the degree of X chromosome inactivation and the presence of modifier genes. Because it is a complex disorder involving many organ systems, it is likely that recovery of RTT patients will involve a combination of treatments. Precision medicine is warranted to provide the best efficacy to individually treat RTT patients.

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“…The fluidity by which MeCP2 manipulates neuronal function bestows on it a unique feature that has made the precise pathophysiology of the autonomic dysregulation seen in patients with RTT difficult to understand. Nevertheless, autonomic dysregulation has been explored in patients with RTT [ 17 , 39 – 46 ]. One hypothesis is that unrestrained vagal tone causes a sympatho-vagal imbalance that is considered unique to patients with RTT [ 36 ].…”

Section: Autonomic Dysfunction In Rett Syndromementioning

confidence: 99%

Key issues in Rett syndrome: emotional, behavioural and autonomic dysregulation (EBAD) - a target for clinical trials

Singh

Santosh

2018

Orphanet J Rare Dis

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Complex neurodevelopmental disorders need multi-disciplinary treatment approaches for optimal care. The clinical effectiveness of treatments is limited in patients with rare genetic syndromes with multisystem morbidity. Emotional and behavioural dysregulation is common across many neurodevelopmental disorders. It can manifest in children across multiple diagnostic groups, including those on the autism spectrum and in rare genetic syndromes such as Rett Syndrome (RTT). There is, however a remarkable scarcity in the literature on the impact of the autonomic component on emotional and behavioural regulation in these disorders, and on the longer-term outcomes on disorder burden.RTT is a debilitating and often life-threatening disorder involving multiple overlapping physiological systems. Autonomic dysregulation otherwise known as dysautonomia is a cardinal feature of RTT characterised by an imbalance between the sympathetic and parasympathetic arms of the autonomic nervous system. Unlocking the autonomic component of emotional and behavioural dysregulation would be central in reducing the impairment seen in patients with RTT. In this vein, Emotional, Behavioural and Autonomic Dysregulation (EBAD) would be a useful construct to target for treatment which could mitigate burden and improve the quality of life of patients.RTT can be considered as a congenital dysautonomia and because EBAD can give rise to impairments occurring in multiple overlapping physiological systems, understanding these physiological responses arising out of EBAD would be a critical part to consider when planning treatment strategies and improving clinical outcomes in these patients. Biometric guided pharmacological and bio-feedback therapy for the behavioural and emotional aspects of the disorder offers an attracting perspective to manage EBAD in these patients. This can also allow for the stratification of patients into clinical trials and could ultimately help streamline the patient care pathway for optimal outcomes.The objectives of this review are to emphasise the key issues relating to the management of EBAD in patients with RTT, appraise clinical trials done in RTT from the perspective of autonomic physiology and to discuss the potential of EBAD as a target for clinical trials.

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Cardiovascular Autonomic Dysfunction in Children and Adolescents With Rett Syndrome

Cited by 23 publications

References 22 publications

Impaired autonomic function in adolescents born preterm

Impaired autonomic function in adolescents born preterm

Treating Rett syndrome: from mouse models to human therapies

Key issues in Rett syndrome: emotional, behavioural and autonomic dysregulation (EBAD) - a target for clinical trials

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